Iopamidol (The Merck Index, XIII Ed., 2001, No. 5073) (N,N′-Bis[2-hydroxy-1-(hydroxymethyl)methyl]-5-[[(2S)-2-hydroxy-1-oxopropyl]-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide, is a contrast agent widely used for diagnostic investigations by X-ray.
Its synthesis is known since the eighties and disclosed e.g. in GB1472050. Since then, alternative processes for its preparation have been developed, for example starting from 5-nitroisophthalic acid, suitably reduced to the corresponding amino derivative, for example by means of catalytic hydrogenation, and after that iodinated on the benzene ring so as to form the corresponding 2,4,6-triiodo derivative. This one, for example in the presence of thionyl chloride, is then converted into the corresponding dichloride of 5-amino-2,4,6-triiodoisophthalic acid (see i.e.: WO 96/037458, WO 96/037459, WO 96/016927 and WO 96/036590).
The process for Iopamidol synthesis from the dichloride of 5-amino-2,4,6-triiodoisophthalic acid (I) and its variants (see for example: WO 96/037460, U.S. Pat. No. 5,362,905, WO 97/047590, WO 98/24757, WO 98/028259 and WO 99/058494) may be schematically represented as follows:

is converted into the corresponding compound of formula (II) in the presence of (S)-2-acetyloxypropionyl chloride. The so prepared intermediate compound of formula (II) is then converted into the acetyl-Iopamidol of formula (III) in the presence of 2-amino-1,3-propandiol (serinol).
At the end, the hydrolysis of the compound of formula (III) and the subsequent purification of the obtained product allow to isolate Iopamidol, compound of formula (IV) (European Pharmacopoeia 6.0 Ed. January 2008: 1115).
Even if different process variants have been disclosed and used for Iopamidol preparation, one of the key reagents, common to all the synthesis, is still the (S)-2-acetyloxypropionyl chloride, the purity of which is crucial to achieve the Pharmacopoeia requirements on the final end product.
The preparation of this reagent is disclosed for example in EP773925, where the starting reagent is sodium lactate, in the presence of HCl and acetic anhydride, in acetic acid; the so obtained (S)-2-acetyloxypropionic acid intermediate is then chlorinated with thionyl chloride to give the corresponding (S)-2-acetoxypropionyl chloride. Sodium lactate, commercially available but quite expensive, has to be transformed in situ, at first, into lactic acid by adding hydrochloric acid gas and then acetylated. The addition of HCl leads to the formation of sodium chloride that has to be removed by mechanical means, usually by filtration. These steps have been summarized in EP2230227 (prior art discussion).
The prior art also discloses few variants of the (S)-2-acetyloxypropionic acid synthesis and its chlorination. For example, Zhang J. et al. Fine and Specialty Chemicals, 2011, 6:26-29, discloses the preparation of (S)-2-acetyloxypropionyl chloride starting from lactic acid, using acetyl chloride as an acetylating agent. The low yields do not allow an industrial scale development.
WO2012/155676 discloses the synthesis of (S)-2-acetyloxypropionic acid from lactic acid (85%) in toluene, in the presence of acetic acid and sulfuric acid as catalyst, the reaction requires several hours at reflux.
U.S. Pat. No. 2,399,595 describes some approaches to the synthesis of (S)-2-acetyloxypropionic acid by reacting pure lactic acid, with various mixtures of acetic acid and/or acetic anhydride, typically in the presence of acid catalysts (HCl or sulfuric acid) and/or organic solvents (benzene). In the only example where an aqueous solution (80%) of lactic acid is used, this is reacted with acetic acid in the presence of benzene and concentrated sulfuric acid.
US 2004/0110974 describes the synthesis of (S)-2-acetyloxypropionic acid from 85% lactic acid in acetic acid and with H2SO4 in a continuous mode; water is removed by acetic acid, which is also used as the acetylating agent. According to this process, a large excess of acetic acid is used to minimize dimerization.
WO 2014/090650 discloses a process for preparing (S)-2-acetyloxypropionic acid which comprises distilling water from an aqueous solution of lactic acid with a counter stream of acetic acid continuously fed into the system, reacting lactic acid in acetic acid with acetic anhydride and recovering the (S)-2-acetyloxypropionic acid by distillation of acetic acid.
The Applicant has now found a new method for preparing (S)-2-acetyloxypropionic acid wherein the sole reactants employed are an aqueous solution of lactic acid and acetic anhydride. The preparation method comprises in particular introducing only acetic anhydride and substantially anhydrous lactic acid in the reaction environment of a preparation assembly, while acetic acid is formed in situ (essentially as a by-product of the acetylation reaction between acetic anhydride and lactic acid). According to the invention, the acetic acid formed in situ is advantageously employed as a vapour stream for stripping water from the lactic acid solution fed into the preparation assembly, in order to provide the desired essentially anhydrous lactic acid to the reaction environment.